Keenova Therapeutics has dosed the first patient in a pivotal Phase 3 trial evaluating XIAFLEX, or collagenase clostridium histolyticum, as a nonsurgical treatment for adults with hammer toe, taking an already established collagen-degrading biologic into a musculoskeletal indication where current management ranges from footwear modifications and orthotics to corrective surgery. The double-blind, randomized and placebo-controlled KN3835-313 trial is expected to enroll approximately 550 participants across about 35 US sites, making this considerably more than an exploratory indication-extension study. Its primary endpoint asks whether XIAFLEX can improve the ability to straighten the affected toe by reducing flexion contracture at the proximal interphalangeal joint, while secondary measures examine foot function, activity limitations and patients’ assessments of hammer toe severity.
The development strategy builds on a mechanism that has already been clinically validated in two fibrotic conditions. XIAFLEX contains two purified collagenases derived from Clostridium histolyticum and has been marketed in the United States since 2010 for Dupuytren’s contracture and since 2013 for Peyronie’s disease. The enzymes hydrolyze collagen in its native triple-helical structure, disrupting the collagen-rich cords or plaques responsible for the deformity in those approved uses. Hammer toe presents a different anatomical problem, but Keenova is applying the same fundamental proposition: inject collagenase locally into tissue contributing to a fixed contracture and determine whether enzymatic disruption can restore enough movement to avoid, or at least postpone, surgical correction.
Why is hammer toe a logical but not automatic extension of XIAFLEX?
Hammer toe occurs when one or more lesser toes, most often the second toe, remain abnormally bent at the middle joint because of an imbalance among muscles, tendons and ligaments controlling the digit. Flexible deformities may initially be managed with changes in footwear, orthoses, exercises and other conservative measures, but fixed contractures can become painful, interfere with walking and eventually lead patients toward procedures that release tendons, alter bone or fuse the affected joint. Keenova cites US claims data indicating that approximately two million adults were diagnosed with hammer toe during 2025, although prevalence estimates across the broader scientific literature vary considerably.
The attraction of an injectable treatment is therefore straightforward. A patient whose deformity has progressed beyond what shoe modification can comfortably manage but who does not want surgery currently has relatively limited pharmacological options, and Keenova says there is no FDA-approved nonsurgical drug specifically indicated for hammer toe. If localized collagenase treatment can meaningfully reduce contracture without destabilizing the joint or damaging surrounding structures, XIAFLEX could potentially occupy a treatment position between conservative care and operative correction.
What remains uncertain is whether collagen is as dominant a mechanical driver in hammer toe as it is in the conditions where XIAFLEX is already approved. Dupuytren’s disease contains a palpable collagen-rich cord that can be directly targeted, while Peyronie’s disease involves a defined fibrotic plaque. Hammer toe reflects a more complex musculoskeletal imbalance involving tendons, joint capsule, soft tissue and, in more advanced cases, structural joint changes. A successful Phase 3 result therefore needs to demonstrate that disrupting selected collagenous tissue translates into meaningful functional correction rather than simply producing a measurable change in joint angle.
What exactly will the Phase 3 study need to prove?
The primary endpoint is deliberately mechanical: investigators will determine whether treatment improves the ability to straighten the toe by reducing flexion contracture of the proximal interphalangeal joint. That gives Keenova a relatively objective anatomical measure, but the trial also includes patient-centered outcomes around foot function, activity limitation and overall severity because improving the appearance or angle of a toe without reducing pain or improving walking would provide limited clinical value. Approximately 550 participants give the programme enough scale to characterize both efficacy and less common adverse events more meaningfully than a small proof-of-concept study.
The placebo-controlled design is particularly important because musculoskeletal symptoms can fluctuate and functional outcomes are susceptible to expectations. Neither patients nor investigators should have to infer efficacy from historical surgical outcomes or uncontrolled changes over time. A successful pivotal study should instead show a reproducible separation between active collagenase treatment and placebo on the prespecified contracture endpoint, supported by consistent functional benefit.
Safety will also carry unusual weight because XIAFLEX is intended to act by digesting collagen. The molecule is injected locally precisely to limit its effect to selected pathological tissue, but tendons, ligaments and other healthy structures also contain collagen. Existing XIAFLEX labeling contains substantial warnings appropriate to its approved anatomical uses, making injection technique, dose localization and anatomical selection central components of any new indication.
Why does an indication expansion matter commercially for Keenova?
XIAFLEX is already one of Keenova’s important branded products. The company reported $150 million in XIAFLEX net sales for the second quarter of 2026 and has been actively attempting to extend the collagenase franchise into additional fibrotic and contracture-driven disorders. It recently reported positive Phase 3 results in plantar fibromatosis and has said it plans a supplemental BLA submission for that indication, while the hammer toe programme represents another opportunity to turn an existing biologic, manufacturing platform and physician-education infrastructure into additional revenue without discovering an entirely new molecule.
That strategy can be economically attractive because much of XIAFLEX’s fundamental pharmacology and large-scale manufacturing capability already exists. Each new indication still requires its own evidence and regulatory review, but the company is not starting from preclinical toxicology with an unknown active ingredient. Instead, the development risk centers on whether collagen degradation produces enough clinical benefit in a particular disease and whether the procedure can be standardized safely.
The hammer toe opportunity may also be broader epidemiologically than XIAFLEX’s original orphan or specialist indications, but a larger population does not automatically create a larger drug market. Many people manage hammer toe successfully without intervention, and those progressing to surgery may already have structural disease too advanced for an injection to restore durable alignment. Patient selection could therefore determine whether XIAFLEX becomes a broadly used podiatric procedure or remains a narrower option for contractures meeting specific anatomical criteria.
What would make XIAFLEX genuinely competitive with hammer toe surgery?
Avoiding an operation would be an obvious advantage only if the injection produces durable correction. Surgical procedures can involve recovery, postoperative pain and the risks inherent to an invasive intervention, but they also allow the surgeon to address several anatomical contributors to deformity directly. An injectable collagenase treatment would need to provide enough correction for enough time that patients and podiatrists accept the possibility of recurrence or repeat treatment in exchange for a less invasive pathway.
The secondary endpoints around function and activity may consequently prove as commercially important as the joint-angle endpoint. Physicians will want evidence that patients can wear shoes more comfortably, walk with less limitation and delay or avoid surgery rather than simply demonstrate a statistically improved toe measurement during follow-up.
Keenova has now placed that question into a large pivotal study rather than another exploratory programme. The 550-patient design gives XIAFLEX a path toward a new US indication if the contracture endpoint, functional outcomes and safety profile align. The bigger strategic test is whether enzymatic treatment of fibrosis can become a repeatable platform across multiple musculoskeletal disorders, turning XIAFLEX from a medicine associated mainly with Dupuytren’s and Peyronie’s disease into a broader franchise for locally treatable pathological collagen.
